Researchers at UC San Francisco have taken science a step closer to creating stem cells that are effectively “invisible” to the immune system. This may ultimately lead to the production of “off-the-shelf” stem cell therapies that do not need to be patient matched.
The immune system is a double-edged sword
One of the big challenges in creating effective stem cell therapies is how the immune system responds to cells from other donors and sources. This complex, multilayered system is designed to defend our bodies from the constant onslaught of invading pathogens that we encounter in our daily lives.
While it lets us survive in what would otherwise be a hostile environment, it also presents a problem when we try to introduce cells or organs from an outside source. The immune system is highly aggressive in how it reacts to anything it considers foreign and potentially harmful, which includes not only pathogens but also cells and organs from other people; this often leads to organ rejection.
Currently, doctors treat organ transplant patients with drugs such as rapamycin that suppress the immune system and reduce the chance of organ rejection, but these come with various side effects and leave patients vulnerable to cancer and other diseases, as the immune system is no longer able to respond to danger.
The rejection problem
The stem cell field has struggled in previous years with the problem of rejection. It was originally hoped that the issue had been solved back in 2006 when Yamanaka and other researchers discovered how to create induced pluripotent stem cells (iPSCs), which are capable of specializing into any other kind of cell in the body, by reprogramming adult skin and fat cells . Effectively, Yamanaka and his team were able to take adult cells that had specialized into specific cell types and reset them, which also reset various aging markers in the process. The hope was that these cells, being taken from the patient, would solve the rejection problem.
Unfortunately, even though there were many subsequent attempts to reprogram cells from a patient’s own body to avoid rejection, using them effectively proved to be a challenge. In reality, the success of iPSCs has proven elusive, with results being often being erratic and unpredictable due to some patients’ cells being resistant to reprogramming. It is not currently fully understood why certain cells resist reprogramming and others do not, but the end result is that the reliability, quality, and production of iPSCs is less than ideal.
Moving towards universal stem cells
With this in mind, Dr. Sonja Schrepfer and her team wondered if it is possible to create universal iPSCs that do not have the problem of immune rejection and so can be used in any patient. Their new study details how they used CRISPR-Cas9 gene editing to create pluripotent “universal” stem cells that were not rejected by the host’s immune system when transplanted .
The researchers deleted two of the genes responsible for a family of proteins called major histocompatibility complex (MHC) class I and II. These MHC proteins are present in almost all of our cells, which use these proteins to show patrolling immune cells that they are our own cells and not foreign matter. Cells that lack these MHC proteins are targeted by the immune system, which sends in natural killer (NK) cells to destroy them.
The team then discovered that CD47, a different cell surface protein that signals the garbage-gobbling immune cells called macrophages not to consume our own cells, also appeared to encourage NK cells not to attack. The researchers wondered if CD47 might be the answer to preventing rejection and the resulting immune response, so they used a viral vector to deliver additional copies of the CD47 gene to mouse and human cells that were engineered to lack the MHC surface proteins.
Then, they transplanted these modified mouse stem cells into different, healthy mice, and there was no reaction from their immune systems. The researchers repeated this with human stem cells transplanted into mice that were engineered to have immune systems closer to our own, and, again, there was no immune reaction. This confirmed that the CD47 protein offers a solution to the immune rejection issue.
As a final step, the research team transplanted human heart cells, which were reprogrammed from other cell types, into the engineered mice. They observed that the heart cells were able to survive, attach, and form blood vessels with no immune response from the hosts.
Autologous induced pluripotent stem cells (iPSCs) constitute an unlimited cell source for patient-specific cell-based organ repair strategies. However, their generation and subsequent differentiation into specific cells or tissues entail cell line-specific manufacturing challenges and form a lengthy process that precludes acute treatment modalities. These shortcomings could be overcome by using prefabricated allogeneic cell or tissue products, but the vigorous immune response against histo-incompatible cells has prevented the successful implementation of this approach. Here we show that both mouse and human iPSCs lose their immunogenicity when major histocompatibility complex (MHC) class I and II genes are inactivated and CD47 is over-expressed. These hypoimmunogenic iPSCs retain their pluripotent stem cell potential and differentiation capacity. Endothelial cells, smooth muscle cells, and cardiomyocytes derived from hypoimmunogenic mouse or human iPSCs reliably evade immune rejection in fully MHC-mismatched allogeneic recipients and survive long-term without the use of immunosuppression. These findings suggest that hypoimmunogenic cell grafts can be engineered for universal transplantation.
These universal stem cells have the potential to be far more cost-effective than ordinary iPSCs, as they can be manufactured en masse without the need to create cells specific to each patient, thus eliminating the higher costs of doing so. This brings the reality of off-the-shelf stem cells one step closer to the clinic as well as potentially solving the issue of immune rejection, which has plagued the stem cell field for decades. Given that stem cell reprogramming and replacement are cornerstones of repair-based approaches to aging, this new research is a considerable step forwards.
 Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. cell, 126(4), 663-676.
 Deuse, T., Hu, X., Gravina, A., Wang, D., Tediashvili, G., De, C., … & Davis, M. M. (2019). Hypoimmunogenic derivatives of induced pluripotent stem cells evade immune rejection in fully immunocompetent allogeneic recipients. Nature Biotechnology, 1.